1. Field of the Invention
The present invention generally relates to biodegradable polymer compositions, in particular those containing both phosphoester linkages in the polymer backbone and chargeable groups linked to the backbone through a P—N bond. The polymers of the invention are useful for drug and gene delivery, particularly as carriers for gene therapy and for the delivery of protein drugs.
2. Background
Gene therapy has been progressively developed with the hope that it will be an integral part of medical modalities in the future. Gene delivery system is one of the key components in gene medicine, which directs the gene expression plasmids to the specific locations within the body. The control of gene expression is achieved by influencing the distribution and stability of plasmids in vivo and the access of the plasmids to the target cells, and affecting the intracellular trafficking steps of the plasmids (Mahato, et al., 1999, Pharmaceutical perspectives of nonviral gene therapy, Adv. Genet. 41: 95-156). An ideal gene delivery carrier should be bioabsorable, non-toxic, non-immunogenic, stable during storage and after administration, able to access target cells, and efficient in aiding gene expression. As many studies demonstrated, the limitations of viral vectors make synthetic vectors an attractive alternative. Advantages of non-viral vectors include non-immunogenicity, low acute toxicity, versatility, reproducibility and feasibility to be produced on a large scale. Cationic liposome and cationic polymers are the two major types of non-viral gene delivery carriers. Cationic lipids self assemble into organized structures include micelles, plannar bilayer sheets, and lamellar vesicles. Through the condensation process, liposomes and cationic polymers form complexes with DNA due to charge interaction. A large variety of liposomal compositions have been developed for gene delivery (Chesnoy and Huang, 2000. Structure and function of lipid-DNA complexes for gene delivery, Annu. Rev. Biophys. Biomol. Struct. 29: 27-47). An effective liposome vector generally composed of a positively charged lipid (e.g. cationic derivatives of cholesterol and diacyl glycerol, quaternary ammonium detergents, lipid derivatives of polyamines, etc.) and a neutral helper lipid (e.g. dioleoyl phosphatidylethanolamine (DOPE) or dioleoyl phosphotidylcholine (DOPC)). Despite early excitement, there are serious limitations to most cationic lipid systems. Several observations have suggested that liposomal systems are relatively unstable after the administration. Significant toxicity upon repeated use has been shown to be associated to liposomal vectors, especially the fusogenic phospholipid (neutral lipid), include the down regulation of PKC dependent immunomodulator synthesis, macrophage toxicity, neurotoxicity and acute pulmonary inflammation (Filion and Phillips, 1998, Major limitations in the use of cationic liposomes for DNA delivery, Int. J. Pharm. 162: 159-170).
Because of the limitations of viral vectors, cationic lipids, cationic polymers as the basis of gene delivery systems have gained increasing attention recently. A number of polycations have been reported to effect transfection of DNA, including poly-L-lysine, poly-L-ornithine, poly(4-hydroxy-L-proline ester), polyiminocarbonate containing cyclodextrin, poly[α-(4-aminobutyl)-L-glycolic acid], polyamidoamines, polyamidoamine dendrimers, chitosan, polyethylenimine, poly(2-dimethylaminoethyl methacrylate), etc. Significant progress has been made in the development of polymer based systems, especially biodegradable polymers that have lower toxicity and can mediate gene transfection via condensing DNA into small particles and protecting DNA from enzymatic degradation. Nevertheless, searching for a safer and more efficient gene carrier still remains a major challenge in the field of non-viral gene delivery.